The goal of this revision application is to add a metabolomics study to the project called ?Interdisciplinary research to understand the interplay of diabetes, cerebrovascular disease, and Alzheimer?s disease? (DiCAD; RF1AG051556; PI: Brickman, Luchsinger [contact], Moreno; 10/01/15-08/31/20), in Years 4 and 5 of the parent project, after collection of most biospecimens is completed in Year 3. The proposed new metabolomics procedures are not included in the parent grant. This project will enhance metabolomics discovery in the DiCAD project and the M2OVE-AD and AMP-AD consortia by implementing the targeted metabolomic discovery approaches in humans from the Alzheimer?s disease metabolomics consortium (ADCM) in human and mice studies in DiCAD. In this application we propose to (a) study whether we can reproduce metabolomics signatures found by the ADCM in the Alzheimer?s Disease Neuroimaging Initiative (ADNI), which is a cohort sampled on the basis of cognitive diagnoses, in the DiCAD cohort, which is a community-based cohort of late middle-aged subjects without dementia, who are well phenotyped from a demographic, anthropometric, clinical history, cognitive, cerebrovascular disease and Amyloid, Tau, and Neurodegeneration (A/T/N) standpoint; (b) study whether we can reproduce the ADNI metabolomics signatures in mouse models of AD, diabetes, and appropriate controls, with and without stroke, with outcomes analogous to the human cohort, but with biospecimens from brain, gut and liver in addition to blood, which will allow to discern mechanisms and functional correlates through cross-species modeling. We will accomplish these goals through the following specific aims: 1. To discover the metabolomics signatures associated with Alzheimer?s disease (AD) with and without cerebrovascular disease (CVD) in humans and mice. For both humans and mice, we will use 2 targeted metabolomics platforms that have been informative in defining signatures related to cognition, cognitive decline and brain imaging changes in ADNI, Biocrates P180 and Biocrates Bile Acids. Biocrates P180 kits measure 180 metabolites covering lipids, acylcarnitines, and amines. Biocrates Bile Acids Kits measure 20 primary and secondary bile acids end products of cholesterol metabolism and clearance that involve gut microbiome human co-metabolism. 2. To explore in new experiments in sphingomyelin synthase (SMS) knockout mice, not included in the parent project, the functional impact of lowering SM levels, similar to those found in human AD. We will study mice with abnormalities of different grades in de novo synthesis of SM. We will relate the metabolomics profile of 2 brain structures (frontal cortex and cerebellum) and plasma.